1. Schizophrenia (SZ) and smoking. We previously found that dorsal anterior cingulate (dACC) striatum resting state functional connectivity (rsFC) are independently associated with nicotine addiction and psychiatric illness. We hypothesized that SZ smokers will have greater dysfunction in smoking-related insular and dACC circuits than healthy control smokers (HCS) independent of smoking severity, consistent with an inherent disease-related weakening of smoking-related circuits. Nicotine challenge was used to show that decreased rsFC in identified circuits reflects addiction trait and is not affected by pharmacological state. Subjects received 2 resting state fMRI scans: placebo or nicotine patch. Using anatomically defined insula and dACC seeds, we found significant negative correlations between smoking severity and rsFC between insula, dACC and striatum in both groups. Further, SZ smokers showed additive reductions in circuit strength between dACC and insula compared to HCS, independent of smoking severity. Nicotine challenge did not significantly alter rsFC in insula-dACC-striatal circuits. Reduced rsFC strength between the insula, dACC and striatum is associated with nicotine addiction severity in both groups. 2. Systems level modeling of fMRI data have demonstrated dysfunction of large-scale brain networks in SZ. Anomalies associated with SZ could be due to diffuse pathology across multiple networks or dysfunction at a converging control(s) common to these networks. The anterior insula (aI) has been shown to modulate activity in the default network (DN) and central executive network (CEN) in healthy individuals and is an integral part of the salience network (SN). We applied seed-based rsFC analysis and two effective connectivity techniques, Granger analysis and structural equation modeling to resting state fMRI data, and found compelling, corroborative evidence of disruption of right aI modulation of DN and CEN networks in SZ. The strength of this aI modulation predicts cognitive performance and severity of psychosis in SZ, implicating the aI as an emergent pathophysiological gateway in this brain disorder. 3. Default Network: Imaging studies indicate that the DN maintains mental processes during passive rest such as when the mind wanders; failure to deactivate this activity leads to acute performance errors and attentional lapses. The ability to manipulate DN activity pharmacologically would be a novel approach to improve cognition in disease populations. Enhanced attention by large-dose nicotine may be mediated by enhanced task-induced deactivation of the DN. We aim to determine whether DN activity is modulated by nicotinic tone. Effects of nicotine patch and the nicotinic antagonist mecamylamine on DN activity during cognitive task performance is measured in nonsmokers (HCS, SZ) using fMRI. DMN modulation by nicotine in nicotine-nave subjects may show that the effect does not reflect reversal of withdrawal state, providing proof of concept needed for clinical application. Nicotine is expected to aid task-induced deactivation of DN, particularly under conditions that invite task-independent thought and attentional lapses, which may enhance performance. Mecamylamine should weaken task-induced DN deactivation, and may impair performance and increase variability. Demonstrating robust effects of nicotinic receptor ligands on DN activity would be a novel model of nicotinic agonists with cognitive-enhancing potential. 4. Attentional problems in SZ may be linked to abnormal regulation of the DN of resting brain functions. The DN maintains a level of broad watchfulness toward the external environment, presumably as a safety mode when attention isnt directed to specific external stimuli. To test whether these defects are based on disruption of this sentinel function of the DN, SZ and HC performed a visuospatial attention paradigm that manipulates the spatial predictability of a target signal. When the target is completely unpredictable and attention is kept broad and undirected, this task shows activity in central regions of the DN, and is disproportionately impaired in SZ. Using fMRI, the trial-by-trial association of reaction time with DN activity was measured. We expect target signals to be spatially unpredictable and activity of these regions related to task performance, only in HC. Thus, broad spatial monitoring in controls is expected to be aided by sentinel function of the DN, but absent in SZ. Responses will be compared to task trials that enable advance-orienting of attention to trials that require broad spatial monitoring. Linking specific attention deficits to specific neural systems helps reduce the complexity of cognitive deficits in SZ to a small number of underlying issues, which may be more amenable to treatment and easily linked to specific gene variants. Thus, the sentinel function of the DN may be aided by drugs similar to nicotine and could be a robust biomarker of treatment to enhance cognitive function. 5. Smoking and cognitive enhancement: The prevalence of smoking among SZ is about 3x higher than in the general population. Neurocognitive deficits in SZ appear to be partly based on nicotinic acetylcholine receptor abnormalities. Nicotine enhances perceptual processing, psychomotor speed, alertness, attention and mnemonic processes. Thus, smoking in SZ represents an attempt to self-medicate cognitive dysfunction. To test this, smokers (half SZ) were randomized to: smoke ad libitum, nicotine and placebo patch. A visuospatial attentional cue task, and a singleton distractor task was performed post-patch. In both tasks, the patch robustly shortened reaction time in both groups. Additionally, in controls, free-smoking performance was almost identical when on patch, suggesting optimized performance by self-administering nicotine via cigarettes. In contrast, performance while free-smoking in SZ resembled performance with placebo more than with nicotine patch. This suggests that SZ did not derive optimal nicotine concentrations from free-smoking. Nicotine plasma concentrations are being analyzed to see whether SZ had lower nicotine intake when free-smoking. Larger blood nicotine levels may be needed by SZ to achieve the same cognitive benefits. On a Reasons for Smoking questionnaire, a larger percentage of SZ indicated the amount they smoked depended on their need to concentrate, indicating they were aware of the cognitive-enhancing potential of smoking. 6. Prenatal Drug Exposure (PDE): We examined the consequences of exposure to drugs in utero in adolescents to the neurobiological mechanisms of risky decision-making, working memory (WM) and rsFC. Results indicate while there is no behavioral difference between PDE and healthy adolescents on risky decision making, PDE adolescents show widespread increased activation in areas including cingulate, insula, inferior frontal gyrus, posterior temporal, parietal and occipital regions. Network circuit analysis using graph theory indicates reduced global and local efficiency in PDE adolescents. Volumetric analyses indicate PDE adolescents have greater hippocampal volume that correlates negatively with measures of memory function and reduced bilateral BA45 volume that correlates positively with a cautious response style in an inhibitory control task.